Alzheimer's disease (AD) is the leading cause of dementia in aged individuals. Of the pathologic hallmarks of AD is the formation of senile plaques, mostly composed of aggregated beta-amyloid (Abeta) peptide. Studies in vitro and in cell culture implicate the tissue plasminogen activator/plasminogen (tPA/pig) system in AD. (Aggregated Abeta peptide stimulates the activity of the tPA enzyme. The addition of aggregated Abeta peptide also leads to the elevation of tPA mRNA and plasmin, formed from plasminogen by tPA, can cleave the Abeta peptide attenuating the neurotoxicity.) The tPA system contributes to excitotoxic neuronal degeneration, a type of cell death observed in AD. This proposal will to address the effect of the tPA/pig system in the deposition of the Abeta peptide and the progression of AD. First, the clearance of Abeta will be investigated in mice deficient in molecules of the tPA/pig system (i.e. tPA-/- pig-/-). Additionally, by crossing mouse models engineered to exhibit AD pathology (Abeta plaques and cognitive deficit) with tPA-/- or pig-/- mice, we hope to define the effect of the tPA system n AD pathogenesis. The final part of this study will focus on the therapeutic possibilities that arise from the effect of the tPA/pig system in the progression of Alzheimer's disease.